As the population continues to age, degenerative ocular diseases become increasingly common and create tremendous burden on the health care system. Vision impairment in the elderly with AMD takes away an average of 5 quality years of life. Age-related macular degeneration (AMD) represents a large market with ~2 million patients and another ~8 million people at risk in the U.S. alone. Approximately, 90% of the AMD patients have the dry form of the disease. There are no approved treatments for dry AMD and, thus it represents a potential high impact, targeted area in medicine. The potential market opportunity has been estimated to be up to $4 billion. A pilot study lead by Drs. Merry and Dotson from The Toronto and Oak Ridge Study of Photobiomodulation (TORPA) looked at the effect of photobiomodulation (PBM) in the treatment of dry AMD. The TORPA data for dry AMD shows clinically and statistically significant improvement in visual acuity and contrast sensitivit, immediately after treatment for 6 weeks, demonstrating the potential use of PBM in dry- AMD. The prospective TORPA study combined multiple pre-selected monochromatic wavelengths to stimulate mitochondrial CCO function and suppress VEGF expression. The study conclusions were that LED treatment was a non-invasive, easily administered and safe treatment with no serious adverse events noted. More importantly, the study provides the only 1-year follow-up data of LED effectiveness in dry AMD. Some gradual loss of clinical benefit was seen in the follow-up to one year, suggesting the need to establish a maintenance dosing schedule and the desire to better understand the underlying cellular benefits. Nevertheless, these findings are the first to demonstrate a statistically significant clinical benefit (F(4,68) = 18.86, p < 0.0001) at p to 1 yr in dry AMD patients with PBM. LumiThera was formed from founders with extensive clinical and developmental expertise in photobiomodulation to lead in the commercialization efforts. Multiple wavelength LED clinical and commercial instruments are being designed and built for an ophthalmologist office-based setting. The current SBIR application will establish the cytoprotective effects of PBM in serially expanded human iPS cell-derived RPE cultures exposed to chronic oxidative stress under continuous wave (CW) (Specific Aim 1a) and pulsed wave (PW) (10 or 100 Hz, 20 and 30% duty cycle) (Specific Aim 1b) irradiation. Specific aim 2 will establish the magnitude of benefit of multiple LED wavelengths on cellular endpoints including retinal bioenergetics, oxidative stress, inflammation and Drusen components. Specific Aim 3 will establish the in vivo therapeutic benefits of PBM in three established mouse models manifesting an AMD-like phenotype. The results from these studies will provide for optimization of clinical dosing parameters and establish the mechanisms of action of PBM in the retina in vitro and in vivo. The findings will provide the basic safety and scientific foundation for a pivotl trial with a novel non-invasive, non-pharmaceutical therapy for dry-AMD.